Zeb1 mediates injury-induced mesenchymal transition in the mouse corneal endothelium in vivo.

Authors

Martin Heur, Simone Brabletz, Marc P Stemmler, Thomas Brabletz, JeongGoo Lee

Published in

American journal of ophthalmology. Jun 21, 2026. Epub Jun 21, 2026.

Abstract

To investigate the role of Zeb1 in regulating fibrosis in endothelial mesenchymal transition in the cornea. siRNA knockdown of Zeb1 inhibits FGF2-induced mesenchymal transition in the corneal endothelium. Endothelial cells that undergo mesenchymal transition show increased expression of endothelial-mesenchymal transition associated genes, including COL1, fibronectin and vimentin, and decreased expression of E-cadherin, leading to fibrous retrocorneal membrane formation.
To address potential off-target effects of siRNA knockdown, Zeb1^flox/flox:UBC-CreERT2 mouse was generated to allow for spatiotemporal control of Zeb1 targeting and studying the role of Zeb1 in the corneal endothelium in vivo.
Intracameral injection of 4-hydroxytamoxifen (4-OHT) inhibited Fgf2-induced expression of Zeb1 mRNA and protein in the corneal endothelium of Zeb1^flox/flox:UBC-CreERT2 mouse. Fgf2 and surgical injury-dependent expression of mesenchymal transition-related genes and suppression of E-cadherin were inhibited by conditional targeting of Zeb1 in the mouse corneal endothelium in vivo. Surgical injury led to corneal edema with a central corneal thickness of 189.0 ± 14.6um (injury) vs 92.3 ± 2.8um (control), and injury-induced edema was significantly attenuated by Zeb1 targeting in the corneal endothelium with a central corneal thickness of 182.2 + 15.5um (injury) vs 106.8 ± 11.1um (injury + 4-OHT), F = 120.9, p < 0.00001. Moreover, conditional targeting of Zeb1 also inhibited injury-dependent RCM formation in the mouse corneal endothelium in vivo.
These results suggest that ZEB1 signaling could be targeted for inhibiting retrocorneal membrane formation and anterior segment fibrosis, and could be leveraged to treat certain forms of corneal blindness without relying on transplantation.

PMID:
42323978
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

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